REVIEWS Passive immunotherapy of viral infections: ‘super-antibodies’ enter the fray Laura M. Walker1 and Dennis R. Burton2–4 Abstract | Antibodies have been used for more than 100 years in the therapy of infectious diseases, but a new generation of highly potent and/or broadly cross-reactive human monoclonal antibodies (sometimes referred to as ‘super-antibodies’) offers new opportunities for intervention. The isolation of these antibodies, most of which are rarely induced in human infections, has primarily been achieved by large-scale screening for suitable donors and new single B cell approaches to human monoclonal antibody generation. Engineering the antibodies to improve half-life and effector functions has further augmented their in vivo activity in some cases. Super-antibodies offer promise for the prophylaxis and therapy of infections with a range of viruses, including those that are highly antigenically variable and those that are newly emerging or that have pandemic potential. The next few years will be decisive in the realization of the promise of super-antibodies. The use of antibodies to ameliorate the adverse clini­ then the generation of fully human antibodies by vari­ cal effects of microbial infection can be traced back to ous techniques described below. Such antibodies have the late 19th century and the work of von Behring and been largely applied in the fields of oncology and auto­ Kitasato on the serum therapy of diphtheria and tetanus immunity. Only a single antiviral mAb, the RSV­specific (reviewed in REFS 1,2). In these settings, the antibodies antibody palivizumab, is in widespread clinical use. act to neutralize bacterial toxins. Therapies followed in The reasons for this have been discussed elsewhere1,3–6, which serum antibodies were targeted directly against although perhaps the most important reasons are the bacterial and then viral pathogens. For viral pathogens, fairly high cost of the production of mAbs, the difficul­ 1Adimab LLC, Lebanon, enriched polyclonal IgG molecules from immunized ties of administration and a belief that antibodies are New Hampshire 03766, USA. animals were shown to be effective in prophylaxis, largely effective only in a prophylactic setting, which can 2Department of Immunology and Microbiology, Center for and even prophylaxis after exposure, for a number of be achieved for many viruses by vaccination. HIV/AIDS Vaccine viruses, including hepatitis A virus, hepatitis B virus, However, as we discuss here, an increasing number Immunology and Immunogen hepatitis C virus, herpes simplex virus, measles virus, of antiviral antibodies with quite remarkable properties Discovery, The Scripps rabies virus, respiratory syncytial virus (RSV), smallpox in terms of potency and/or cross reactivity with other Research Institute, La Jolla, virus and varicella zoster virus. In general, the effective­ viruses or strains of the same virus are being isolated. California 92037, USA. 3International AIDS Vaccine ness of antibody preparations declined with the dura­ These so­called super­antibodies are changing our Initiative Neutralizing tion of infection such that they were often regarded as understanding of what we can hope to achieve with anti­ Antibody Center, The Scripps poor therapeutic options. Of course, the major antiviral bodies against microbial infection in the clinic. Increased Research Institute, La Jolla, strategy of the 20th century was vaccination. potency can greatly reduce the unit costs of treatment, California 92037, USA. 4Ragon Institute of Over the latter part of the 20th and early part of make alternative routes of administration feasible and Massachusetts General the 21st century, there have been major developments extend the effective half­life of the antibody. Increased Hospital, Massachusetts in our understanding of antibodies and our ability to cross reactivity can allow us to consider targeting multi­ Institute of Technology and manipulate them. The advent of hybridoma technol­ ple viruses with single antibodies. Antibody engineering Harvard University, ogy in 1976 provided a reliable source of mouse mono­ can impact both potency and cross reactivity and can Cambridge, Massachusetts 02139, USA. clonal antibodies (mAbs), the first impact of which was greatly extend the half­life of super­antibodies. [email protected]; not on antibody therapy but on the characterization In this Review, we discuss how new approaches have [email protected] of cells through the definition of cell surface markers. fuelled the identification of super­antibodies, where doi:10.1038/nri.2017.148 Broad implementation of mAbs in therapy had to wait and how such antibodies may be best applied and future Published online 30 Jan 2018 until the development of humanized mouse antibodies and directions for the field. NATURE REVIEWS | IMMUNOLOGY VOLUME 18 | MAY 2018 | 297 ©2018 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. REVIEWS Super-antibody discovery Lassa viruses, extensive glycosylation on the surface Many acute viral infections induce robust neutralizing Env proteins results in masking of conserved neutral­ antibody responses in the large majority of individuals. izing epitopes15,32. In cases where super-antibodies are In general, these viruses show little evidence for evasion present at low frequency within immune repertoires, of antibody responses, and we have referred to them large-scale donor screening and high-throughput B cell as ‘evasion lite’ viruses7. Typically, they either display isolation platforms have proved to be critical for the dis­ limited antigenic variability in their surface protein (or covery of super-antibodies. Over the past several years, proteins) or show considerable variability but never­ technological advances in these two areas have led to theless express immunodominant, conserved epitopes. the identification of large numbers of super-antibodies, Examples of viruses in this category include measles mostly from infected individuals, against a plethora of virus, poliovirus, chikungunya virus and RSV8–11. The viral pathogens. life cycle of these viruses presumably does not dictate immune evasion. For these types of viruses, the iso­ Large-scale donor screening. In the case of HIV, which lation of super-antibodies from immune donors has has served as a prototype virus for many studies in this been achieved in a fairly straightforward manner8,9,12–14. field33, systematic selection of donors with broadly However, some viruses have evolved mechanisms to neutralizing serum responses has proved to be critical evade effective neutralizing antibody responses (termed for the identification of super-antibodies. Before 2009, ‘evasion strong’ viruses) and induce such responses at the HIV field had been operating with a handful of much lower levels. Effective responses in the context of bnAbs, all of which were limited either in breadth or in infection with highly antigenically variable viruses refers potency34. A number of factors complicated the iden­ not only to their neutralization potency but also to their tification of bnAbs, including the inefficiency of tradi­ effectiveness against diverse circulating global isolates, tional approaches to mAb discovery, the small fraction often referred to as breadth. For these viruses — includ­ of B cells that secrete bnAbs and the limited availability ing HIV, influenza virus, Ebola virus and Lassa virus of samples from donors who had developed broad and — only a proportion of infected individuals, sometimes potent neutralizing serum responses. Beginning in 2005, quite small, will generate broad and potent neutralizing the problem of limited samples was addressed by estab­ antibody responses15–21. Furthermore, within these indi­ lishing donor screening programmes to identify HIV- viduals, potent broadly neutralizing antibody (bnAb) infected individuals with broadly neutralizing serum specificities generally constitute only a small fraction of responses to serve as source material for the generation the antigen-specific memory B cell pool. of bnAbs18,19,35,36. In one of the largest studies, ~1,800 For example, only a small percentage of HIV‑infected HIV‑infected individuals from Australia, Rwanda, individuals develop broad and potent serum responses Uganda, the United Kingdom and Zambia were screened over time, and B cell cloning efforts have demonstrated for broadly neutralizing sera using a reduced pseudo­ that bnAbs generally comprise <1% of the HIV enve­ virus panel representative of global circulating HIV iso­ lope (Env)-specific memory B cell repertoire22. Although lates19. A subset of individuals, termed ‘elite neutralizers’, there are probably multiple factors that contribute to the was identified that exhibited exceptionally broad and low abundance of bnAbs within these individuals, the potent neutralizing serum responses and was therefore intrinsic nature of the viral Env protein likely has a key prioritized for bnAb isolation. role. The HIV Env protein has evolved a multitude of Over the past 8 years, mining of these and sim­ mechanisms to evade bnAb responses, including decoy ilar samples has led to the identification of dozens of forms of Env, enormous antigenic variability, an evolving remarkably broad and potent HIV super-antibodies37–41. glycan shield, immunodominant and variable epitopes Careful selection of donors with desirable serum profiles and poorly accessible conserved epitopes23. Furthermore, has also enabled the isolation of rare super-­antibodies most HIV-specific